supplementary data - diabetes care · 10/3/2018 · antwerpen uza dienst endocrinologie, edegem,...
Post on 22-Oct-2020
4 Views
Preview:
TRANSCRIPT
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
Supplementary Appendix:
This appendix has been provided by the authors to give readers additional information about their work.
Supplement to: Rosenstock J et al. Empagliflozin as Adjunct Therapy to Insulin in Type 1 Diabetes:
The EASE Trials
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
Table of Contents:
Clinical trial site list in EASE-2 and EASE-3
Ethics approvals and patient consenting
EASE-2 and EASE-3 list of inclusion and exclusion criteria
Guidance on insulin dose adjustment
Ketoacidosis risk mitigation strategies used in EASE-2 and EASE-3
Ketoacidosis event identification and case categorization based on adjudication
Clinical course of events in the fatal ketoacidosis case
Definitions of hypoglycemia
Case definitions and categorization of events undergoing severe hypoglycemia adjudication
List of safety laboratory tests
Independent committees overseeing safety and event adjudication
EASE-2 and EASE-3 primary, key secondary and safety end points
Statistical analysis details and testing hierarchy
Devices use: Blood glucose-ketone meter, e-diary and continuous glucose monitoring
Supplementary Figure S1: Schematic design of EASE-2 and EASE-3 trials
Supplementary Figure S2: CONSORT diagrams of patient disposition in EASE-2 and EASE-3
Supplementary Figure S3: Glycated hemoglobin effectiveness analysis
Supplementary Figure S4: Body weight - over time graphs and analyses
Supplementary Figure S5: Systolic blood pressure – over time graphs and analyses
Supplementary Figure S6: Diastolic blood pressure – over time graphs and analyses
Supplementary Figure S7: EASE-2 and EASE-3 CGM-based glucose time in range and inter-quartile analyses
Supplementary Figure S8: Total daily insulin dose - over time graphs and analyses
Supplementary Figure S9: Total daily basal insulin dose - over time graphs and analyses
Supplementary Figure S10: Total daily bolus insulin dose - over time graphs and analyses
Supplementary Figure S11: Fasting Plasma glucose – over time graphs and analyses
Supplementary Figure S12: Waist circumference – over time graphs and analyses
Supplementary Figure S13: Safety analysis of hypoglycemia during week 1-4 of treatment
Supplementary Figure S14: Net benefit analysis
Supplementary Figure S15: Explanations for differences in urinary glucose excretion in T1D vs T2D
Supplementary Table S1: Clinical characteristics of adjudicated certain ketoacidosis
Supplementary Table S2: Analysis of adjudicated certain or potential ketoacidosis based on sex and insulin
therapy
References for supplementary information
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
CLINICAL TRIAL SITE LIST IN EASE-2 AND EASE-3
EASE-2:
Sultan Linjawi, Coffs Endocrine & Diabetes Centre, New South Wales, Australia; Michael d’Emden, Royal
Brisbane & Women’s Hospital, Endocrinology Research Unit, Queensland, Australia; Claire Morbey, AIM
Centre Level 1, New South Wales, Australia; Rudolf Prager, Hospital Hietzing Krankenhaus Hietzing mit NZR 3.
Medizinische Abteilung, Wien, Austria; Bernhard Ludvik, KH Rudolfstiftung, 1. Med.Abt. Wein Krankenanstalt
Rudolfstiftung inkl. Semmelweis Frauenklinik, Wein, Austria; Heinz Drexel, VIVIT Instit.am LKH Feldkirch
Abteilung fuer Innere Medizin und Kardiologie, Feldkirch, Austria; Christian Hengl, LKH Steyr Innere Medizin
II, Steyr, Austria; Pieter Gillard, UZ Leuven – Campus Gasthuisberg I.G. Endocrinologie, Leuven, Belgium;
Chris Vercammen, Bonheiden – HOSP Imelda, Imelda ZH Bonheiden endocrinology, Bonheiden, Belgium;
Fabienne Lienart, La Louvière - UNIV CHU Tivoli CHU Tivoli Diabétologie, La Louvière, Belgium; Corinne
Debroye, Brussels – UNIV UZ Brussel, UZ Brussel Diabeteskliniek, Brussel, Belgium; Marie Strivay, Liège -
HOSP CHR de la Citadelle CHR de la Citadelle Service, Liège, Belgium; Luc Van Gaal, Edegem - UNIV UZ
Antwerpen UZA Dienst Endocrinologie, Edegem, Belgium; Bernard Jandrain, Centre Hospitalier Universitaire
de Liège Diabétologie/Unite de Pharmacologie Clinique, Liège, Belgium; Laurent Crenier, ULB Hopital Erasme,
Service d’Endocrinologie, Bruxelles, Belgium; Bruno Lapauw, UNIV UZ Gent Endocrinologie en
Stofwisselingsziekten, Gent, Belgium; Ann Verhaegen, Merksem – HOSP ZNA Jan Palfijn, Merksem, Belgium;
Eric Weber, Arlon – HOSP Sud Luxembourg – Vivalia, Arlon, Belgium; Ronald Goldenberg, LMC Clinical
Research Inc. (Thornhill), Thornhill, Ontario, Canada; Robyn Houlden, Kingston General Hospital, Kingston,
Ontario, Canada; Bruce Perkins, Mount Sinai Hospital Lunenfeld-Tanenbaum Research Institute, Toronto,
Ontario, Canada; Thomas Ransom, Nova Scotia Health Authority, Centre for Clinical Research Endocrinology
Research and Metabolism, Halifax, Nova Scotia, Canada; Buki Ajala, LMC Clinical Research Inc. (Thornhill),
Thornhill, Ontario, Canada; Vincent Woo, Winnipeg Regional Health Authority, Health Sciences Centre
Winnipeg, Diabetes Research Group, Winnipeg, Manitoba, Canada; Jean-Francois Yale, The Research Institute of
the Mc Gill University Health Centre-Glen Site, Montreal, Quebec, Canada; Jean-Louis Chiasson, Centre
Hospitalier de l’universite de Montreal-Pavillon R, Montreal, Quebec, Canada; David Miller, Royal Jubilee
Hospital, Victoria, British Columbia, Canada; Josias Badenhorst, The Bailey Clinic, Red Deer, Alberta, Canada;
Martin Prazny, General University Hospital in Prague (VFN), Praha, Czech Republic; Jiri Lastuvka, Masaryk
Hospital, Usti nad Labem, Czech Republic; Vladimir Lelek, Diabetology and Internal Practice Dr. Vladimir
Lelek, Slany, Czech Republic; Steen Anderson, Nordsjællands Hospital Kardiologisk, Nefrologisk &
Endokrinologisk Afdeling, Hillerød, Denmark; Henrik Ullits Anderson, Steno Diabetes Center Copenhagen,
Gentofte, Denmark; Leif Breum, Sjællands Universitetshospital Køge Medicinsk afdeling, Endokrinologisk
Afsnit, Køge, Denmark; Tina Schou Anderson, Aalborg Sygehus Syd Aalborg Universitetshospital Klinik
Medicin, Aalborg, Denmark; Per Løgstrup Poulsen, Aarhus Universitetshospital Medicinsk endokrinologisk afd.
M, Aarhus C, Denmark; Jorma Strand, Terveystalo Oulu, Diapolis, Oulu, Finland; Lassi Nelimarkka, TYKS
Turun yliopistollinen keskussairaala Sisätautien klinikka, Turku, Finland; Sakari Nieminen, IteLasaretti, Kuopio,
Finland; Jean-Pierre Courrèges, HOP de Narbonne, Narbonne, France; Thierry Delmas, HOP Brabois,
Vandoeuvre-lès-Nancy, France; Céline Lukas-Croisier , Hôpital Robert Debré Service d'Endocrinologie, de
Diabétologie et de Nutrition, Reims, France; Yves Reznik, HOP Côte de Nacre CHU de Caen-Centre Hospitalier
Universitaire, Caen, France; Didier Gouet, HOP Saint Louis Diabétologie endocrinology, France; Pierre
Serusclat, HOP les Portes du Sud, Diabéto, Vénissieux France; Veronika Wenzl-Bauer, Allgemeinmedizinische
und Diabetologische Schwepunktpraxis, Rehlingen-Siersburg, Germany; Bärbel Hirschhäuser, Praxis Dr.
Hirschhäuser, Saarbrücken, Germany; Alexander Segner, Praxis Dr. Segner, St. Ingbert Praxis für
Allgemeinmedizin und Innere Medizin, Oberwürzbach, Germany; Karl-Michael Derwahl, ikfe - Institut für
klinische Forschung und Entwicklung Berlin GmbH, Berlin, Germany; Rolf Göbel, Gemeinschaftspraxis, Asslar
Schwerpunktpraxis Diabetes, Asslar, Germany; Gerhard Klausmann, Studienzentrum Klausmann Studienzentrum
Aschaffenburg, Aschaffenburg, Germany; Joachim Müller, Ambulanzzentrum Schweinfurt Gemeinschaftspraxis
Dr. J. Müller, Dr. S. Appelt & Kollegen, Schweinfurt, Germany; Christine Kosch, Praxis Dr. Kosch, Pirna
Diabetologische Schwerpunktpraxis, Pirna, Germany; Helga Eufemia Zeller-Stefan, InnoDiab Forschung GmbH
Institut für Stoffwechselerkrankungen, Essen, Germany; Max Nieuwdorp, Academisch Medisch Centrum
(AMC), Amsterdam, Netherlands; Suat Simsek, Noordwest Ziekenhuisgroep, Alkmaar, Netherlands; Adriaan
Kooy, Bethesda Ziekenhuis Hoogeveen, Hoogeveen, Netherlands; Janneke Wiebolt, Sint Franciscus Gasthuis,
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
Rotterdam, Netherlands; Ruud van Leendert, Albert Schweitzer Ziekenhuis Zwijndrecht, Zwijndrecht,
Netherlands; K Hoogenberg, Martini Ziekenhuis, Groningen, Netherlands; MMC Hovens, Rijnstate Hospital,
Arnhem, Netherlands; Elisabeth Qvigstad, Oslo Universitetssykehus HF, Aker Sykehus - Avd. Endokrinologisk
Poliklinikk Postboks Nydalen, Oslo, Norway; Hilde Selsås, Helse Møre og Romsdal HF, Ålesund sjukehus
Medisinsk Poliklinikk for Diabetes, Ålesund, Norway; Archana Sharma, Akershus Universitetssykehus HF
Department of Endocrinology, Lørenskog, Norway; Trine E. Finnes, Sykehuset Innlandet HF, Avd. Hamar
Endokrinologisk seksjon, Hamar, Norway; Katarzyna Klodawska, NBR Polska, Warsaw, Poland; Bogna
Wierusz-Wysocka, Karol Marcinkowski Poznan University of Medical Sciences, Poznan, Poland; Ewa
Skokowska, NZOZ Specialized Ambulance “MEDICA”, Lublin, Poland; Maria Gorska, Medical University of
Bialystok Clinical Department of Endocrinology, Diabetology & Int Dis., Białystok, Poland; Malgorzata
Arciszewska, NZOZ Specjalistyczny Osrodek Internistyczno-Diabetologiczny, Białystok, Poland; Antoni
Sokalski, NZOZ Centrum Medyczne AESKULAP, Private practice, Radom, Poland; Stanisław Mazur, Centrum
Medyczne Medyk Private Practice, Rzeszow, Poland; Andziej Dyczek, Dobry Lekarz, Spec. Med. Clinics, Private
Practice, Krakow, Poland; Jordi Mesa, Hospital Vall d’Hebron, Barcelona, Spain; Carlos Brotons, CAP Sardenya
Servicio de Atención Primaria / Medicina de Familia, Barcelona, Spain; Juan José Linares, Hospital de la
Inmaculada Concepción Clinica Inmaculada Concepcion Medicina Interna. Unidad de HTA y Síndrome
Metabólico, Granada, Spain; FranciscoTinahones Madueño, Hospital Virgen de la Victoria, Malaga, Spain;
Santiago Durán García, Hospital Universitario Nuestra Señora De Valme, Sevilla, Spain; Cristobal Morales
Portillo, Hospital Universitario Virgen Macarena, Sevilla, Spain; Fernando Gómez Peralta, Hospital General de
Segovia, Segovia, Spain; Johan Jendle, Centralsjukhuset, Karlstad Centralsjukhuset Endokrin- och
diabetescentrum, Karlstad, Sweden; Katarina Berndtsson Blom, Ladulaas Kliniska Studier, Borås, Sweden; Bo
Liu, Läkarhuset, Vällingby Läkarhus, Vällingby, Sweden; Lee-Ming Chuang, National Taiwan University
Hospital Department of Oncology, Taipei, Taiwan; Yi-Jen Hung, Tri-Service General Hospital, Taipei, Taiwan;
Chien-Ning Huang, Chung Shan Medical University Hospital, Taichung, Taiwan; Kai-Jen Tien, Chi Mei, Medical
Center, Tainan, Taiwan; Ching-Chu Chen, China Medical University Hospital, Taichung, Taiwan; Mark Evans,
Cambridge University Hospitals NHS Foundation Trust – Addenbrooke’s Hospital, Cambridge, United Kingdom;
Ken Darzy, East and North NHS Trust – Queen Elizabeth II Hospital, Welwyn Garden City, United Kingdom;
Melanie Davies, Leicester General Hospital, Leicester, United Kingdom; Mohammed Huda, The Barts Health
NHS Trust, Royal London Hospital, London, United Kingdom; Ben Field, Surrey & Sussex Healthcare NHS
Trust East Surrey Hospital, Surrey, United Kingdom; Peter Mansell, Nottingham University Hospitals NHS Trust,
Queen’s Medical Centre, Nottingham, United Kingdom; Asif Ali, Milton Keynes University Hospital –
Diabetes/Endocrinology Department, Buckinghamshire, United Kingdom; Ponnusamy Saravanan, George Eliot
Hospital NHS Trust Diabetes Centre, Nuneaton, United Kingdom; John McKnight, Wellcome Trust Clinical
Research Facility, Edinburgh, United Kingdom; Paul D. Rosenblit, Diabetes/Lipid Management & Research
Center, Huntington Beach, California, United States; Sam Lerman, Jellinger and Lerman, MD, PA dba The
Center for Diabetes and Endocrine Care, Fort Lauderdale, Florida, United States; Betsy Palal, Palm Research
Center, Inc. Las Vegas, Nevada, United States; Jack D. Wahlen, Advanced Research Institute, Ogden, Utah,
United States; Yehuda Handelsman, Metabolic Institute of America, Tarzana, California, United States; Leslie
Klaff, Rainier Clinical Research Center, Inc., Renton, Washington, United States; Peter N. Weissman, Baptist
Diabetes Associates, PA., Miami, Florida, United States; Kerem Ozer, Texas Diabetes & Endocrinology, P.A.,
Round Rock, Texas, United States; Hiralal Maheshwari, Midwest CRC, Crystal Lake, Illinois, United States;
Joanna Thuy Van Do, University Clinical Investigators, Inc., Tustin, California, United States; Juan Pablo Frias,
National Research Institute, Los Angeles, California, United States; Leonard R. Zemel, Creekside Endocrine
Associates, PC., Denver, Colorado, United States; Timothy S. Bailey, AMCR Institute Inc., Escondido,
California, United States; Gregg Gerety, Albany Medical College, Division of Community Endocrinology,
Albany, New York, United States; John Chip Reed, Endocrine Research Solutions, Inc., Roswell, Georgia, United
States; Carl Vance, Rocky Mountain Diabetes and Osteoporosis Center, PA., Idaho Falls, Idaho, United States;
Jeffrey Rothman, University Physicians Group Research Division, Staten Island, New York, United States;
Lucinda Bateman, Bateman Horne Center, Salt Lake City, Utah, United States; Adeniyi Olabiyi Odugbesan,
Physicians Research Associates, LLC., Lawrenceville, Georgia, United States; David Klonoff, Mills-Peninsula
Health Services – Diabetes Research Institute, San Mateo, California, United States; Luis Soruco, Northwest
Endo Diabetes Research, LLC., Arlington Heights, Illinois, United States; William Reid Litchfield, Desert
Endocrinology Clinical Research Center, Henderson, Nevada, United States; Ronald Graf, MultiCare Institute for
Research and Innovation, Tacoma, Washington, United States; Peter Bressler, North Texas Endocrine Center,
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
Dallas, Texas, United States; Michelle Zaniewski-Singh, Michelle Zaniewski MD, PA., Houston, Texas, United
States; Kathryn Jean Lucas, Diabetes and Endocrinology Consultants, PC., Morehead City, North Carolina,
United States; Anuj Bhargava, Iowa Diabetes and Endocrinology Research Center, West Des Moines, Iowa,
United States; Claire Baker, Diabetes & Endocrine Associates, PC., Omaha, Nebraska, United States; Howard
A. Baum, Diabetes and Obesity Clinical Trials Center, Nashville, Tennessee, United States; Robert J. Silver,
Southern New Hampshire Diabetes and Endocrinology, Nashua, New Hampshire, United States; Meenakashi
Iyer, The Lindner Center for Research and Education at The Christ Hospital, Cincinnati, Ohio, United States;
Kenneth M. Gross, The Polyclinic, Seattle, Washington, United States; David Rickenbeck Sutton Jr., East Coast
Institute for Research, LLC., Jacksonville, Florida, United States; Larry D. Stonesifer, Larry D. Stonesifer MD
Inc., PS, Washington, United States
EASE-3:
Anthony Roberts, SA Endocrine Research P/L, Keswick, South Australia, Australia; Parind Vora, Lyell McEwin
Hospital Clinical Trials Unit, Elizabeth Vale, South Australia, Australia; Murray Gerstman, Eastern Clinical
Research Unit, ECRU Maroondah, East Ringwood, Victoria, Australia; Sultan Linjawi, Coffs Endocrine &
Diabetes Centre, New South Wales, Australia; Lawrence Leiter, St. Michael’s Hospital, Toronto, Ontario,
Canada; Stewart Harris, Centre for Studies in Family Medicine Western University, London, Ontario, Canada;
Josias Badenhorst, The Bailey Clinic, Red Deer, Alberta, Canada; Guy Tellier, Omnispec Recherche Clinique
Inc., Mirabel, Quebec, Canada; John Weisnagel, Clinique des maladies Lipidiques de Quebec, Quebec, Quebec,
Canada; Ron Sigal, Richmond Road and Diagnostic Treatment Centre, Calgary, Alberta, Canada; Christopher
Kovacs, Eastern Health (MUN) Division of Endocrinology – Health Science Centre, St. John’s, Newfoundland,
Canada; George Michael Tsoukas, Applied Medical Informatics Research INC., Westmount, Quebec, Canada;
Elena Silhova, University hospital Kralovske Vinohrady, II. Clinic of Internal Medicine – Dept Diabetology,
Prague, Czech Republic; Emilia Malicherova, ResTrail s.r.o. Diabetology Ambulance, Prague, Czech Republic;
Dagmar Bartaskova, Milan Kvapil s.r.o. Diabetology Ambulance, Prague, Czech Republic; Vlasta Kutejova,
AIDIN VK s.r.o. Department Diabetology, Hranice, Czech Republic; Dana Burdova, DiaGolfova s.r.o.
Department Diabetology, Prague, Czech Republic; Jitka Hasalova Zapletalova, Diahaza s.r.o. Internal Medicine
Outpatient Clinic – Diabetology, Holesov, Czech Republic; Jana Belobradkova, University Hospital Brno,
Internal Hepatogastroenterology Clinic, Brno, Czech Republic; Kirsi Pietiläinen, HUS, Lihavuustutkimusyksikkö
Biomedicum Helsinski, Helsinki, Finland; Petteri Ahtiainen, Mehiläinen Jyväskylä, Jyväskylä, Finland; Jorma
Lahtela, FinnMedi Oy, Tampere FinnMedi Oy FM 3, Tampere, Finland; Pirkko Korsoff, Satakunnan
Diabetesasema Pori, Pori, Finland; Lassi Nelimarkka, TYKS Turun yliopistollinen keskussairaala Sisätautien
klinikka, Turku, Finland; Samy Hadjadj, HOP de Poitiers, CHU de la Milétrie Centre Investigation, Poitiers,
France; Sylvaine Clavel, HOP Le Creusot -Hôtel Dieu du Creusot Service d'Endocrinologie Site Harfleur, Le
Creusot, France; Olivier Dupuy, HOP Saint Joseph, Endo, Paris G H Paris Saint-Joseph Service de Diabétologie
Endocrinologie, Paris, France; Michel Marre, HOP Bichat, Hôpital Blichat-Claude Bernard Service de
Diabétologie Endocrinologie, Paris, France; Hélène Hanaire, HOP Rangueil, Hôpital Rangueil – CHU Toulouse
Service Diabétologie, Toulouse Cedex, France; Franck Schillo, Hôpital Jean Minjoz, Service d’Endocrinologie,
Diabétologie et Maladies métaboliques, Besancon, France; Nathalie Jeandidier, Hôpital Civil Service
Endocrinologie, Diabétologie, Strasbourg, France; Marcel Kaiser, Diabetologische Schwerpunktpraxis, Frankfurt,
Germany; Thomas Behnke, Zentrum für klinische Studien, Neuwied, Germany; Thomas Haak, Diabetes Zentrum
Bad Mergentheim Diabetes Klinik, Bad Mergentheim, Germany; Andreas Hagenow, Zentrum für klinische
Studien Südbrandenburg GmbH, Elsterwerda, Germany; Elena Henkel, GWT-TUD GmbH, Studienzentrum
Metabolisch-Vaskuläre Medizin, Dresden, Germany; Jost Hilgenberg, Diabetologische Schwerpunktpraxis Leeser
Straße 21, Rehburg-Loccum, Germany; Winfried Keuthage, Schwerpunktpraxis für Diabetes und
Ernährungsmedizin, Münster, Germany; Stephan Maxeiner, Diabetologische hausärztliche Gemeinschaftspraxis
Bosenheim, Bosenheim, Germany; Ludger Rose, Institut für Diabetesforschung, Münster, Germany; Klaus Busch,
Diabeteszentrum DO Diabetologische Schwerpunktpraxis Dortmund, Dortmund, Germany; Helga Eufemia
Zeller-Stefan, InnoDiab Forschung GmbH, Institut für Stoffwechselerkrankungen, Essen, Germany; Iakovos
Avramidis, General Hospital of Thessaloniki “G. Papanikolaou”, Division of Diabetes, Thessaloniki, Greece;
Nikolaos Tentolouris, General Hospital of Athens “Laiko”, Athens, Greece; Stavros Bousboulas, General
Hospital of Nikaia, 3rd Internal Medicine Clinic, Nikaia, Greece; Andromachi Vrionidou-Bompota,
“Korgialeneio-Benakeio” Hellenic Red Cross Hospital, Dept. of Endocrinology, Diabetes and Metabolism,
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
Athens, Greece; Evangelos Rizos, University Hospital of Ioannina, 2nd Pathology Clinic, Ioannina, Greece;
Christos Sambanis, General Hospital of Thessaloniki “Ippokrateio”, 2nd Propedeutic-Internal Medicine Clinic,
Thessaloniki, Greece; Csaba Salamon, Clinfan SMO Ltd., Szekszard, Hungary; Iren Foldesi, Csongrad Country
Dr Bugyi Istvan Hospital Diabetic Outpatient Clinic, Szentes, Hungary; Gyorgy Paragh, University of Debrecen –
1st Internal Clinic, Debrecen, Hungary; Katalin Csomós, CRU Hungary Ltd., Private Practice Miskolc, Miskolc,
Hungary; Tamas Oroszlan, Diabetic Outpatient Clinic, Zala Megyei Szent Rafael Hospital, Zalaegerszeg,
Hungary; Victor Vass, Synexus Magyarorszag Kft. Synexus Hungary Health Care Service Ltd., Budapest,
Hungary; Gyongyi Csecsei, Clinexpert Kft., Budapest, Hungary; Maria Byrne, Mater Misericordiae University
Hospital Metabolic Research Department, Dublin, Ireland; Ezio Ghigo, Ospedale Molinette, AO Città della Salute
e della, CDU Endocrinologia, Diabetologie e Metabolismo Dipartimento di Medicina, Torino, Piemonte, Italy;
Massimo Boemi Dottore, INRCA-IRCCS, U.O.C. Malattie Metaboliche e Diabetologia Centro Diabetico,
Ancona, Marche, Italy; Alberto Di Carlo, Osp. Campo di Marte Servizio di Diabetologia e Malattie Metaboliche
Cittadella della Salute “Campo di Marte”, Lucca, Toscana, Italy; Francesco Dotta, A.O.U. Senese Policlinico
Santa Maria alle Scotte, U.O. di Diabetologia Dipartimento di Medicina Interna, Siena, Toscana, Italy; Simona
Frontoni, Osp. S. Giovanni Calibita Fatebenefratelli, U.O.C. Endocrinologia, Diabetologia e Malattie Metaboliche
Centro Antidiabetico, Roma, Lazio, Italy; Loredana Bucciarelli Dottoressa, IRCCS Gruppo Multimedica Unita’ di
Diabetologia IRCCS “Sesto S. Giovanni-Gruppo Multimedica”, Lombardia, Italy; Dario Pitocco Dottore,
Policlinico Gemelli U.O.C. di Medicina Interna e Angiologia Dipartimento di Scienze Mediche, Roma, Lazio,
Italy; Gabriele Riccardi, Azienda Ospedaliera Universitaria “Federico II” DAI Medicina Clinica U.O.C.
Diabetologia e Malattie del Metabolismo DAI Medicina Clinica, Napoli, Campania, Italy; Umberto Valentini
Dottore, A.O. Spedali Civili di Brescia U.O. di Diabetologia, Brescia, Lombardia, Italy; Renate Helda, Sigulda
Hospital Outpatient Department, Sigulda, Latvia; Valda Stalte, VSV Centrs, Stalte Private Practice, Talsi, Latvia;
Dace Teterovska, Dace Teterovska Doctor’s Private Practice in Endocrinology, Ogre, Latvia; Sigita Pastare,
Zemgale’s Centre of Diabetes, Jelgava, Latvia; Valdis Pirags, P. Stradins Clinical University Hospital
Endocrinology Center, Riga, Latvia; Anatolijs Lucenko, A. Lucenko’s Internist & Endocrinologist Doctor’s
Practice, Liepaja, Latvia; Inta Leitane, Riga Health Centre, Private Practice, Riga, Latvia; Guillermo Gonzalez
Galvez, Instituto Jaliscience de Inv. en Diabetes y Obesidad, S.C., Jalisco – Guadalajara, Mexico; Maricela Vidrio
Velazquez, Unidad de Investigación Clínica Cardiometabólica Departamento de Nutrición, Metabolismo y
Diabetología Departamento de Nutrición, Metabolismo y Diabetología, Jalisco-Guadalajara, Mexico; Guillermo
Antonio Llamas Esperon, Hospital Cardiologica Aguascalientes, Aguscalientes, Mexico; Ricardo Choza Romero,
Clínica EndocrInol en Diabetes Obesidad y Tiroides (DOT), Aguascalientes, Mexico; María del Rosario
Arechavaleta Granell, Unidad de Patologia Clinica, Jalisco- Guadalajara, Mexico; Jan Westerink, Universitair
Medisch Centrum Utrecht UMC Utrecht Locatie AZU, Utrecht, Netherlands; P.A.M. de Vries, Ziekenhuisgroep
Twente locatie Almelo ZGT Almelo, Almelo, Netherlands; T. van Bemmel, Gelre Ziekenhuizen Apeldoorn,
Apeldoorn, Netherlands; P.C. Oldenburg-Ligtenberg, Meander Medisch Centrum, Amersfoort, Netherlands; M.
Alhakim, EB FlevoResearch BV, locatie Utrecht, Utrecht, Netherlands; Suat Simsek, Noordwest
Ziekenhuisgroep, Alkmaar, Netherlands; Russell Scott, Lipid and Diabetes Research Group, Don Beaven Medical
Research Centre, Christchurch Hospital Campus, Christchurch, New Zealand; Edward Watson, South Pacific
Clinical Trials, Auckland, New Zealand; Ragnar Joakimsen, Universitetssykehuset Nord-Norge, Tromsø,
Norway; John Graham Cooper, Stavanger Helseforskning, Stavanger, Norway; Cecilie Wium, Oslo
Universitetssykehus HF, Lipidklinikken, Rikshospitalet, Oslo, Norway; Hans Olav Høivik, M3 Helse AS, Hamar
Avd. For Medisinsk Forskning, Hamar, Norway; Elzbieta Bandurska-Stankiewicz, Regional Specialist Hospital in
Olsztyn Clinic of Endocrinology, Diabetics and Internal Medicine, Olsztyn, Poland; Jaroslaw Opiela, Omedica
Medical Centre, Poznan, Poland; Grazyna Cieslik, Medical Centre Pratia Krakow, Krakow, Poland; Grzegorz
Dzida, Independent Public Clin.Hosp.no1 Lublin Dept. Internal Diseases, Lublin, Poland; Anna Tochman-Gawda,
Witold Chodzko Institute of Rural Medicine Department of Diabetology, Lublin, Poland; Iwona Kobielusz-
Gembala, Clinical Research Center Medicome, private practice, Oswiecim, Poland; Violetta Szostek-Gawel,
NZOZ Med-Art. Specialist Clinics, Zory private practice, Zory, Poland; Aleksandra Madej-Dmochowska,
Medical Centre Pratia Gdynia Private practice, Gdynia, Poland; Jolanta Kitowska-Koterla, Medical Centre Pratia
Katowice I, Katowice, Poland; Grazyna Popenda, DiabSerwis S.C., Chorzow private practice, Chorzow, Poland;
Agnieszka Tiuryn-Petrulewicz, Medical Centre Pratia Warszawa, Medica Pro Familia S.A. private practice,
Warszaw, Poland; Maciej Malecki, University Hospital in Krakow, Department of Metabolic Diseases, Krakow,
Poland; Jorge Dores, Centro Hospitalar do Porto, EPE CHP, Porto, Portugal; Rosa Ballesteros, Centro Hospitalar
da Cova da Beira, Covilhã, Portugal; Cristina Rogado, APDP-Associação Protectora dos Diabéticos de Portugal,
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
Lisboa, Portugal; Celestino Neves, Centro Hospitalar São Joao, EPE Serviço de Endocrinologia, Portugal;
Cristina Roque, ULSAM, EPE – Hospital de Santa Luzia Serviço Endocrinologia, Viana do Castelo, Portugal;
Marta Alves/Olinda Marques, Hospital de Braga-Escala Braga Serviço Endocrinologia, Braga, Portugal; Maria
João Oliveira, Centro Hospitalar de Vila Nova Gaia/ Espinho Serviço de Endocrinologia, Vila Nova de Gaia,
Portugal; Ciprian Constantin, Dr. Carol Davila Central Military Emergency University Hospital Diabetes,
Bucharest, Romania; Gabriela Doina Negrisanu, Medical Centre Dr Negrisanu SRL, Timisoara, Romania;
Nicoleta Mihaela Mindrescu, SC Nicodiab SRL, Bucharest, Romania; Dana Cosma, SC Pelican Impex SRL
Cabinet Nr. 11 Diabetes Dept., Nutrition & Metabolic Diseases, Oradea, Romania; Adriana Dumitrescu, SC
“Sanatatea Ta” Medical Centre SRL, Bucharest, Romania; Ruslan Sardinov, Policlinic No. 1 of Russian Academy
of Sciences Dept. Endocrinology Dept., St. Petersburg, Russian Federation; Anton Edin, City of Outpatient
department no. 107, Clinical Pharmacology, St. Petersburg, Russian Federation; Natalia Vorokhobina, City
Hospital Saint Elizaveta Dept. Endocrinology, St. Petersburg State Health Care, St. Petersburg, Russian
federation; Nina A. Petunina, City Clinical Hospital No. 67, Moscow, Russian Federation; Vitaly Baranov,
Medical Academy named after I. Mechnikov Dept. Endocrinology, St. Petersburg, Russian Federation; Elena
Arefyeva, CJSC “Polyclinic complex”, Dept. Endocrinology, St. Petersburg, Russian Federation; Lawrence
Distiller, Dr. L. A. Distiller Centre for Diabetes & Endocrinology, Johannesburg, South Africa; Hilton Kaplan,
Dr. Hilton Kaplan, Cape Town, South Africa; Luthando Adams, LCS Clinical Research Unit, LCS Cosmo Day
Clinic, Johannesburg, South Africa; Paul Abrahams, VX Pharma (Pty) Ltd., Pretoria Syzygy Clinical Research
Services, Pretoria, South Africa; Samantha du Toit/ Lize Maritz, TREAD Research, Cape Town, South Africa;
Shaifali Joshi, Diabetes Care Centre, Pretoria, South Africa; Olga González, Hospital General universitario
Gregorio Marañon, Madrid, Spain; Francisco Javier del Cañizo, Hospital Universitario Infanta Leonor, Madrid,
Spain; Martin López de la Torre, CM+ Investigación, CM Avances Médicos, Granada, Spain; Francisco Javier
Ampudia, Hospital Clínico de Valencia, Valencia, Spain; Alfonso Soto González, Hospital A Coruña, Coruña,
Spain; Santiago Durán García, Endo-Diabesidad-Clínica Durán & Asociados, Sevilla, Spain; Juan José Linares,
Hospital de la Immaculada Concepción, Granada, Spain; Isabel Serrano Olmedo, Hospital Universitario Virgen
Macarena, Sevilla, Spain; Magnus Löndahl, Skånes universitetssjukhus Endokrinmottagningen, Lund, Sweden;
Dan Curiac, CTC Sahlgrenska Universitetssjukhuset, Göteborg, Sweden; Martin Ferletta, Karlskoga lasarett,
Karlskoga, Sweden; Peter Kalén, Sjukhuset, Ängelholm Diabetes/Endokrinsektionen, Ängelhom, Sweden; Bo
Liu, S3 Clinical Research Centers, Vällingby, Sweden; Pratik Choudhary, King’s College London Weston
Education Centre, London, United Kingdom; Nick Oliver, St. Mary’s Hospital Clinical Research Network,
London, United Kingdom; Thozhukat Sathyapalan, Hull Royal Infirmary Diabetes, Endocrinology and
Metabolism Research Centre, Hull, United Kingdom; Vijayaraman Arutchelvam, The James Cook University
Hospital Academic Centre, Middlesbrough, United Kingdom; Luigi Gnudi, Guy’s Hospital Dept. of Diabetes and
Endocrinology, London, United Kingdom; Stuart Little, Royal Victoria Infirmary, The Newcastle upon Tyne
Hospitals, United Kingdom; Gerry Rayman, Ipswich Hospital Diabetes Centre, Ipswich, United Kingdom; Susana
Gonzalez, Bradford Royal Infirmary, Department of Diabetes and Endocrinology, Bradford, United Kingdom;
Helen Partridge, Royal Bournemouth and Christchurch Hospital NHS Foundation Trust, Bournemouth, United
Kingdom; Melanie Davies, Leicester Diabetes Centre, Leicester, United Kingdom; Peter Mansell, Queen’s
Medical Centre, Deptartement of Diabetes and Endocrinology, Nottingham, United Kingdom; Ponnusamy
Saravanan, George Eliot Hospital Diabetes Centre, Nuneaton, United Kingdom; Bruce Trippe, Healthscan
Clinical Trials LLC, Montgomery, Alabama, United States; Kristin Castorino, William Sansum Diabetes Center,
Santa Barbara, California, United States; Thanh Minh Nguyen, Solutions Through Advanced Research Inc.,
Jacksonville, Florida, United States; Kashif Latif, AM Diabetes and Endocrinology Center, Bartlett, Tennessee,
United States; Andrew P. Brockmyre, Holston Medical Group, Bristol, Tennessee, United States; David Huffman,
University Diabetes and Endocrine Consultants, Chattanooga, Tennessee, United States; Lindsay Harrison, Texas
Diabetes & Endocrinology, P.A., Austin, Texas, United States; Rodney Stout, Holzer Clinic LLC, Gallipolis,
Ohio, United States; Glenn Blaise Gatipon, Sestron Clinical Research, Marietta, Georgia, United States; Michael
Shanik, Endocrine Associates of Long Island, PC, Smithtown, New York, United States; Julio Rosenstock, Dallas
Diabetes and Endocrine Center, Dallas, Texas, United States; Bresta Miranda, University of Miami Diabetes
Research Institute, Miami, Florida, United States; Wendell Miers, Kentucky Diabetes Endocrinology Center,
Lexington, Kentucky, United States; Dan Lender, Texas Health Physicians Group, Dallas, Texas, United States;
Linda Gaudiani, Marin Endocrine Care and Research Inc., Greenbrae, California, United States; Yshay
Shlesinger, NorCal Endocrinology and Internal Medicine, San Ramon, California, United States; Antonio Pinero-
Pilona, Suncoast Clinical Research Inc., New Port Richey, Florida, United States; Donald Eagerton, Strand
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
Physician Specialists dba Carolina Health Specialists, Myrtle Beach, South Carolina, United States; Stephen
Aronoff, Research Institute of Dallas, Dallas, Texas, United States; Paul Norwood Jr., Valley Research, Fresno,
California, United States; Philip Levin, MODEL Clinical Research, Baltimore, Maryland, United States; Anna
Chang, John Muir Physician Network Clinical Research Center, Concord, California, United States; Bruce Bode,
Atlanta Diabetes Associates, Atlanta, Georgia, United States; Firas Akhrass, Endeavor Clinical Trials, LLC, San
Antonio, Texas, United States; Samer Nakhle, Palm Research Center Inc., Las Vegas, Nevada, United States;
Luis Carlos Quintero, International Research Associates, LLC., Hialeah, Florida, United States; Paresh Dandona,
Diabetes Endocrinology Research Center of Western New York, Williamsville, New York, United States; Kristi
Silver, University of Maryland Medical Center, Baltimore, Maryland, United States; Ahmed M. Awad, Clinical
Research Consultants, LLC., Kansas City, Missouri, United States; Zachary Freedman, Endocrine-Diabetes Care
and Resource Center, Rochester, New York, United States; Neda Rasouli, University of Colorado Hospital,
Aurora, Colorado, United States; James LaRocque, Virginia Endocrinology Research, Chesapeake, Virginia,
United States; Clinton Corder, COR Clinical Research, LLC., Oklahoma City, Oklahoma, United States; Ronald
Watts, Eagles Landing Diabetes & Endocrinology, Stockbridge, Georgia, United States; Anand Mehta, Pacific
Research Partners, LLC., Oakland, California, United States; Luis Soruco, Northwest Endo Diabetes Research,
LLC., Arlington Heights, Illinois, United States; William Reid Litchfield, Desert Endocrinology Clinical
Research Center, Henderson, Nevada, United States; Kathryn Jean Lucas, Diabetes and Endocrinology
Consultants, PC., Morehead City, North Carolina, United States; Adeniyi Olabiyi Odugbesan, Physicians
Research Associates, LLC., Lawrenceville, Georgia, United States
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
ETHICS APPROVALS AND PATIENT CONSENTING
The EASE-2 and EASE-3 clinical trials were carried out in compliance with the protocol, the ethical principles
laid down in the Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for GCP,
relevant BI SOPs and relevant regulations. Standard medical care (prophylactic, diagnostic and therapeutic
procedures) remained in the responsibility of the treating physician of the patient.
Trials were initiated only after all required legal documents had been reviewed and approved by the respective
ethics board and competent authority body according to national and international regulations. The same applied
for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent was obtained from each patient (or the patient’s
legally accepted representative) according to ICH / GCP and based on the regulatory and legal requirements of the
participating country.
Prior to the initiation of any trial-related procedure, all patients were informed about the trial verbally and in
writing by the investigator. The patient was allowed sufficient time to consider participation in the trial and to ask
questions concerning the details of the trial. Each patient signed and dated an informed consent form according to
the local regulatory and legal requirements. The signed informed consent form and additional documents for
patient information were retained by the investigator as part of the trial records. Each patient received a copy of
the signed informed consent form and additional documents for patient information.
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
EASE-2 AND EASE-3 LIST OF INCLUSION AND EXCLUSION CRITERIA
Inclusion criteria:
1. Signed and dated written informed consent by the date of Visit 1 in accordance with Good Clinical Practice (GCP) and local legislation
2. Male or female patient receiving insulin for the treatment of documented diagnosis of T1D for at least 1 year at the time of Visit 1
3. Fasting C-peptide value of < 0.7 ng/mL (0.23 nmol/L) at Visit 2 measured by the central laboratory 4. Use of, and be willing, based on the Investigator’s judgement, to continue throughout the duration of the
trial, either:
a. MDI of insulin consisting of at least one basal insulin injection and at least three daily bolus injections OR
b. CSII of any insulin type, with at least 5 months experience of using CSII prior to Visit 1 For both MDI and CSII, the total daily insulin dose must be ≥ 0.3 U/kg and ≤ 1.5 U/kg at Visit 1
5. HbA1c ≥ 7.5% and ≤ 10.0% at Visit 5 measured by the central laboratory, and provided that the patient’s HbA1c does not increase by > 0.5% between Visit 1 and Visit 5
6. Based on the Investigator’s judgement patient must have a good understanding of his/her disease and how to manage it, and be willing and capable of performing the following study assessments (assessed at
Visits 1-5 and just before randomisation):
patient-led management and adjustment of insulin therapy
reliable approach to insulin dose adjustment for meals, such as carbohydrate counting
reliable and regular home-based blood glucose monitoring
recognise the symptoms of DKA, and reliably monitor for ketones
implementation of an established “sick day” management regimen 7. Age ≥ 18 years at Visit 1 8. Body Mass Index (BMI) of ≥ 18.5 kg/m2 at Visit 1 9. eGFR ≥ 30 mL/min/1.73 m² as calculated by the CKD-EPI formula, based on creatinine measured by the
central laboratory at Visit 1
10. Women of child-bearing potential* must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently
and correctly. Such methods should be used throughout the study and the patient must agree to periodic
pregnancy testing during participation in the trial. A list of contraceptive methods meeting these criteria
provided in the patient information
*Women of child-bearing potential are defined as follows: Any female who has experienced menarche
and is not post-menopausal (defined as at least 12 months with no menses without an alternative medical
cause) or who is not permanently sterilised (e.g. hysterectomy, bilateral oophorectomy or bilateral
salpingectomy)
11. Compliance with trial medication administration must be between 80% and 120% during the open-label placebo run-in period, to be judged before randomisation
12. Only in EASE-3: To participate in the optional CGM substudy: Patient is willing to participate in that substudy and eligible based on Investigator’s judgement to perform CGM. CGM substudy is conducted at
the trial site
13. Only in EASE-3: To participate in the optional CGM substudy: Patient is willing, based on the Investigator’s judgement, not to take any paracetamol (acetaminophen) containing drugs throughout the
CGM monitoring periods, since this may falsely raise CGM glucose readings
Exclusion criteria:
1. History of T2DM, maturity onset diabetes of the young (MODY), pancreatic surgery or chronic pancreatitis
2. Pancreas, pancreatic islet cells or renal transplant recipient 3. T1D treatment with any other antihyperglycaemic drug (e.g. metformin, alphaglucosidase inhibitors,
glucagon-like-peptide 1 [GLP-1] analogues, SGLT-2 inhibitors, pramlintide, inhaled insulin, pre-mixed
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
insulins etc.) except subcutaneous basal and bolus insulin within 3 months prior to Visit 1 or any history
of clinically relevant hypersensitivity according to Investigator’s judgement
4. Occurrence of severe hypoglycaemia involving coma/unconsciousness and/or seizure that required hospitalisation or hypoglycaemia-related treatment by an emergency physician or paramedic within 3
months prior to Visit 1 and until randomisation
5. Occurrence of DKA within 3 months prior to Visit 1 and until randomisation at Visit 6 6. Irregular sleep/wake cycle (e.g. patients who habitually sleep during the day and work during the night)
based on Investigator’s judgement
7. Acute coronary syndrome (non-STEMI, STEMI and unstable angina pectoris), stroke or transient ischaemic attack (TIA) within 3 months prior to Visit 1
8. Diagnosis of severe gastroparesis (based on Investigator’s judgement) 9. Diagnosis of brittle diabetes based on Investigator judgement 10. Indication of liver disease, defined by serum levels of either alanine transaminase (ALT), aspartate
transaminase (AST), or alkaline phosphatase above 3 x upper limit of normal
(ULN) at Visit 1 or Visit 5 as measured by the central laboratory
11. Eating disorders such as bulimia or anorexia nervosa 12. Treatment with anti-obesity drugs, weight-loss surgery or aggressive diet regimen leading to unstable
body weight (based on Investigator’s judgement) 3 months prior to Visit 1and until randomisation
13. Treatment with systemic corticosteroids or planned initiation of such therapy at Visit 1and until randomisation. Inhaled or topical use of corticosteroids (e.g. for asthma/chronic obstructive pulmonary
disease) is acceptable
14. Change in dose of thyroid hormones within 6 weeks prior to Visit 1 or planned change or initiation of such a therapy at Visit 1 and until randomisation
15. Only in EASE-2: Patient is unwilling, based on the Investigator’s judgement, to avoid use of paracetamol (acetaminophen) containing drugs throughout the CGM monitoring periods, since this may falsely raise
CGM glucose readings
16. Medical history of cancer or treatment for cancer in the last five years prior to Visit 1. Resected basal cell carcinoma considered cured is exempted
17. Blood dyscrasias or any disorders causing haemolysis or unstable red blood cells (e.g. malaria, babesiosis, haemolytic anaemia) at Visit 1
18. Women who are pregnant, nursing, or who plan to become pregnant whilst in the trial 19. Alcohol or drug abuse within the 3 months prior to Visit 1 that would interfere with trial participation
based on Investigator’s judgement
20. Intake of an investigational drug in another trial within 30 days prior to Visit 1 21. Patient not able to understand and comply with study requirements, including the use of an e-diary, based
on Investigator’s judgement
22. Any other clinical condition that, based on Investigator’s judgement, would jeopardise patient safety during trial participation or would affect the study outcome (e.g. immunocompromised patients who
might be at higher risk of developing genital or mycotic infections, patients with chronic viral infections
etc.)
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
GUIDANCE ON INSULIN DOSE ADJUSTMENT
All patients were required to keep their existing insulin therapy as stable as possible from the first screening visit
until the beginning of the therapy optimization (intensification) period. A 6-week insulin therapy optimization
(intensification) phase was an integral part of the study designs aimed to ensure that, in the investigator’s opinion,
a patient was achieving the best standard of care in accordance with local guidelines. In patients using CSII, and
where considered appropriate, adjustments in type 1 diabetes therapy could be supported by basal rate testing.
Type 1 diabetes therapy optimization was to be complete by the end of the 6-week optimization period so that a
patient’s insulin regimen was as stable as possible as they entered the placebo run-in period and for 2 weeks prior
to randomization.
During periods of stability, in the case of hypoglycemia (e.g. with measured glucose concentration ≤70 mg/dL
(≤3.9 mmol/L)), patients were preferably to ingest additional carbohydrates according to standard practice in the
management of type 1 diabetes. However, a patient’s existing insulin regimen was to be adjusted at any time for
safety reasons if deemed necessary by the investigator, e.g. in the case of persisting hyperglycemia or
hypoglycemia despite adequate carbohydrate intake.
At randomization for patients with an HbA1c of 7.5 to
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
KETOACIDOSIS RISK MITIGATION STRATEGIES USED IN EASE-2 AND EASE-3
Information contained in clinical trial protocol:
Special attention was paid to the prevention of DKA. Investigators were reminded that, due to the mechanism of
action, patients receiving empagliflozin were at risk to underestimate their need for insulin in case of blood sugar
levels within their individual target range. Insulin deficiency might lead to ketoacidosis which could be life-
threatening if not recognized, and appropriately treated. All patients were made aware of this risk and were
instructed not to reduce their insulin intake below Investigator recommendations.
Investigators were reminded that not all criteria in the table below needed to apply for the diagnosis of DKA, and
clinical judgement should also be taken into consideration. General diagnostic criteria for DKA
In addition to performing glucose monitoring, patients were also equipped with an electronic device to determine
their ketone concentration (i.e. a blood glucose monitoring device/meter that is also capable of measuring blood
ketones: beta-hydroxybutyrate (BHB)).
Patients were reminded to test their ketones in case of any symptoms of DKA, e.g. nausea, vomiting, abdominal
pain etc., irrespective of the glucose value. Patients were reminded about the signs and symptoms of DKA, on the
interpretation of ketone values measured via the meter, and on appropriate action to take in the event of increased
ketone levels (see below). In the same way as during routine clinical care, patients were reminded to test for
ketones in case of repeatedly elevated blood glucose levels (e.g. > 200 -240 mg/dL [> 11.1 - 13.3 mmol/L]) which
cannot be explained. Regular (e.g. 2-3 times a week) measurements before breakfast were recommended
throughout the trial from Visit 2. More frequent (e.g. once daily) measurements before breakfast were
recommended during the run-in period and during the first 4 weeks of the treatment period and beyond if agreed
upon with the patient afterwards and if deemed necessary by the Investigator.
In the event of increased ketones, patients were to follow the rules given by their Investigator (e.g. increased fluid
intake and/or insulin bolus; food intake and insulin bolus in case of near-normal blood glucose) or contact their
trial site. In case of deteriorating ketosis, blood glucose and ketone levels were to be checked every 1-2 hours
until they were back in a range considered to be normal for the patient. Patients were instructed to immediately
refer themselves to hospital and/or the Investigator, or to contact an emergency physician, in case of a blood
ketone concentration > 1.5 mmol/L (as indicated in the meter manual). In case of a suspected DKA the
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
Investigator were to ensure that appropriate tests were performed at the earliest opportunity according to local
guidelines, such as a blood gas test (pH, bicarbonate). The results were to be collected on the relevant page of the
electronic case report form.
Investigators were also asked to differentiate clinically deteriorating ketosis/DKA from any mild to moderate
increase of ketones which may be seen due to the mechanism of action of empagliflozin, especially in the fasted
state (e.g. in the morning). Investigators were also asked to carefully select patients for the study in terms of their
ability to comply with ketone measurement requirements. Patients not adhering to the instructions given by the
Investigator were to be retrained at the earliest possible opportunity.
Information contained in the core patient information sheet:
Ketoacidosis is a serious problem that happens to people with diabetes when chemicals called “ketones” build up
in their blood. In extreme cases, it can be fatal. It occurs because people with Type 1 diabetes, like you, make
little or no insulin, and this is the hormone that allows the body to use sugar as a source of energy.
Normally, the body breaks down sugar as a source of energy. However, in people with Type 1 diabetes who do
not make any insulin, the body is unable to use sugar. Instead the body burns fat as a source of energy; but
burning fat can cause too many ketones to be made, and when they build up in the blood, they can be toxic.
There are a few reasons why people might get ketoacidosis (e.g. they are not receiving treatment for their diabetes
since they don’t know they have it, they don’t take their insulin as directed, their insulin pump does not work
correctly etc.). You can reduce your chances of getting ketoacidosis by taking your insulin exactly as directed, and
measuring your blood sugar often to make sure it is not too high or too low. It is also important that you avoid
losing too much water (dehydration) and do not start any diet with very low carbohydrate intake (e.g. the Atkins
diet) since such diets might increase the production of ketones in your body. In case you have already started a
low-carbohydrate diet, you should stop that diet. Reducing alcohol intake also reduces your risks of developing
ketoacidosis.
Your risk for ketoacidosis might be increased if you:
have fever
had ketoacidosis in the past
have, or have had, problems with your pancreas, including pancreatitis or surgery on your pancreas
If any of these points apply to you, you should inform your Study Doctor about them.
Under empagliflozin treatment ketoacidosis could occur even at normal or near-normal glucose levels. Therefore,
you should test your blood ketone level in case of any signs of ketoacidosis, even if your blood glucose levels are
not elevated. These include:
nausea (feeling sick)
vomiting (being sick)
abdominal (tummy) pain
loss of appetite
shortness of breath
rapid heartbeat (tachycardia)
rapid breathing, where you breathe in more oxygen than your body actually needs (hyperventilation)
low blood pressure (hypotension), which can make you feel dizzy and lightheaded
a noticeable smell of ketones on your breath, which is often described as smelling like pear drops or nail varnish remover (not everyone is able to smell ketones)
mental confusion
unconsciousness (coma)
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
general malaise
any other unspecific symptoms
You should also measure your ketone levels in the event of unusually high urine production or pronounced thirst;
however, both are also side effects of the study medication empagliflozin. In addition, ketones should be
measured in case of repeatedly elevated blood glucose levels in the range of more than 200 – 240 mg/dL which
cannot be clearly explained by another reason (e.g. a high carbohydrate intake).
In the event of elevated ketones, you should either follow the rules given to you by your Study Doctor (e.g.
increased fluid intake and/or administration of an insulin bolus; in case of near-normal glucose, consider food
intake with insulin injection), or contact the research site.
If ketoacidosis is suspected, hospital treatment is needed, so you should immediately refer yourself to hospital
and/or your Study Doctor, or contact an emergency physician if you think you might have it.
Information contained in the core patient alert card:
IMPORTANT INFORMATION
Trial No.: Patient No.:_____________
Trial Name: EASE-X: A placebo-controlled clinical study with empagliflozin (SGLT2 inhibitor) in the indication type 1 diabetes mellitus.
Patient Name: __________________________________
Trial Doctor: _______________ :___ _____________
The patient is in a placebo-controlled clinical trial
where empagliflozin (SGLT-2 inhibitor) is being
studied in patients with Type 1 Diabetes
(see REVERSE for important information)
To the treating physician / health care provider:
Diabetic ketoacidosis (DKA) is not uncommon in patients
with Type 1 Diabetes. Please recognise that SGLT-2
inhibitors may modify its presentation: Blood glucose may
appear normal or slightly elevated (
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
KETOACIDOSIS EVENT IDENTIFICATION AND CASE CATEGORIZATION BASED ON
ADJUDICATION
Summary of ketoacidosis trigger identification, adjudication parameters and case definitions:
*2 BHB readings ≥ 3.8 mmol within 24 hours in the absence of symptoms to fulfill the criterion of potential
ketoacidosis
The following are details related to triggers which were used to identify potential ketoacidosis events that were
sent for adjudication:
Any AE where the electronic case report form tick box ‘ketoacidosis’ had been ticked
Selected trigger search terms indicative of ketoacidosis and/or DKA
Selected trigger search terms indicative of acetonemia, when accompanied by reported symptoms suggestive of ketoacidosis, accompanied by a report of hospitalization, and/or reported as an SAE
Any BHB value >1.5 and 1.5 and
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
Case definitions for ketoacidosis adjudication:
KA = ketoacidosis; N/A = data not available
1. For potential KA, a blood BHB value ≥3.8 mmol/L was to be confirmed by an additional measurement ≥3.8 mmol/L within 24 h. A single BHB value ≥3.8 mmol/L without symptoms/suggestive history was to be
regarded as unlikely KA but ketosis.
2.
++/+++ is equivalent to moderate/large, which translates to 1.5 to 2.9 mmol/L blood BHB; ++++ is
equivalent to very large, which translates to ≥3 mmol/L blood BHB.
3. Suggestive history means pump failure, insulin dose omission, illness, improper sick day plan, etc. 4. Typical KA symptoms means neurological (confusion, drowsiness, loss of consciousness, etc.) and non-
neurological symptoms (dehydration, nausea/vomiting, abdominal pain, kussmaul breathing, etc.).
The occurrence of 2 BHB values ≥3.8 mmol/L within 60 min constituted clinically the same reading, it was
required that 2 BHB values ≥3.8 mmol/L within 24 h be separated by more than 60 min (in the absence of any
other parameters) to fulfil the criterion needed for the classification of such an event as potential ketoacidosis.
The CEC assessed ketoacidosis severity using pH per ADA criteria as the primary differentiator (mild: pH 7.25 to
7.30; moderate: pH 7.00 to 7.24; severe: pH
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
CLINICAL COURSE OF EVENTS IN THE FATAL KETOACIDOSIS CASE
A 28-year-old female patient with T1D since 4 years of age
Randomized to empagliflozin 25 mg; patient on insulin pump
Start of event: 106th day after randomization; over 3 days, patient developed flu-like symptoms, sinusitis and high ketones (maximum BHB reading of 4.6 mmol/l)
On the 109th day after randomization, patient had BHB readings of 6.3 mmol/l, blood glucose 190 mg/dl; visited the emergency room due to emesis and sinusitis; the patient did not inform the ER physician about
high BHB or participation in the study; patient was sent home with symptomatic treatment; in the same
evening, paramedics were called due to continued vomiting and abdominal pain, at that time blood
glucose was 337 mg/dl; the patient refused to be hospitalized despite clinical advice
On last day of study medication intake (the 110th day after randomization), the patient was admitted to the hospital in a severe general condition; patient presented with severe acidosis and hyperglycemia; therapy
in the ER included intensive hydration, and insulin infusions (with normalization of blood glucose within
4 hours). The same evening, patient developed bradycardia and later had a cardiac arrest
Patient died after the second resuscitation attempt due to circulatory-respiratory failure secondary to DKA with cerebral edema
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
DEFINITIONS OF HYPOGLYCEMIA
Every episode of blood/plasma glucose ≤ 70 mg/dL (≤ 3.9 mmol/L) was to be documented with the respective
time and date of occurrence. Glucose values used within the criteria for hypoglycaemic events were based on
values measuring using a self-monitoring of blood glucose (SMBG) device and from central laboratory
measurements. Glucose values originating in the SGBM device were subsequently supposed to have been entered
into the patient e-diary by the patient. This included every episode of blood/plasma glucose ≤ 70 mg/dL (≤ 3.9
mmol/L), hypoglycaemia with glucose values < 54 mg/dL (< 3.0 mmol/L) and all symptomatic and all severe
hypoglycaemic events.
For analyses, hypoglycaemia was classified according to the following criteria:
Asymptomatic hypoglycaemia: event not accompanied by typical symptoms of hypoglycaemia but with a measured glucose concentration ≤ 70 mg/dL (≤ 3.9 mmol/L)
Documented symptomatic hypoglycaemia with glucose concentration ≥ 54 mg/dL and ≤ 70 mg/dL (≥ 3.0 mmol/L and ≤ 3.9 mmol/L): event accompanied by typical symptoms of hypoglycaemia
Documented symptomatic hypoglycaemia with glucose concentration < 54 mg/dL (< 3.0 mmol/L): event accompanied by typical symptoms of hypoglycaemia but no need for external assistance
Severe hypoglycaemia: event requiring the assistance of another person to actively administer carbohydrates, glucagon or take other corrective actions. Plasma glucose concentrations may not be
available during an event, but neurological recovery following the return of plasma glucose to normal is
considered sufficient evidence that the event was induced by a low plasma glucose concentration
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
CASE DEFINITIONS AND CATEGORIZATION OF EVENTS UNDERGOING SEVERE
HYPOGLYCEMIA ADJUDICATION
Severe hypoglycemia (also known as severe hypoglycemic episode) was defined as an event requiring the
assistance of another person to actively administer carbohydrate (e.g. intravenously), glucagon or other corrective
actions (please note that assistance of another person means that the patient was genuinely physically unable to
take action). In instances when plasma glucose concentrations during the event were not available, neurological
recovery following the return of plasma glucose to normal was considered sufficient evidence that the event was
induced by a low plasma glucose concentration. This would have applied in theory to fatal hypoglycemic events.
All cases where it was indicated that “assistance was required” (either by the patient in the electronic diary or by
the investigator in AE reporting) were sent to independent Clinical Event Committee for adjudication.
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
LIST OF SAFETY LABORATORY TESTS
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
INDEPENDENT COMMITTEES OVERSEEING SAFETY AND EVENT ADJUDICATION
Data Monitoring Committee:
A Data Monitoring Committee (DMC), independent from the sponsor, was established to assess the progress of
the trial, including unblinded safety data and the critical efficacy end points, at intervals and to recommend to the
sponsor whether to continue, modify, or stop one or more of the trials covered by the DMC charter. Measures
were in place to ensure blinding of the sponsor and all other trial participants. The tasks and responsibilities of the
DMC were specified in the DMC Charter. The DMC maintained written records of all its meetings.
Clinical Event Committee – adjudication of severe hypoglycaemia and ketoacidosis:
An independent external committee was established to adjudicate centrally and in a blinded fashion events
suspected of severe hypoglycaemia and ketoacidosis. The Clinical Event Committee (CEC) evaluated whether
prespecified criteria for severe hypoglycaemia and ketoacidosis case definitions were met, according to the
charter. For any events that qualified for adjudication, trial sites were asked to provide clinical documentation
such as laboratory values, discharge summaries, etc. to support the external event adjudication.
For severe hypoglycaemia, the CEC was to decide if the events sent for adjudication met the definition in the
charter for severe hypoglycaemia (yes, no, or unclassifiable) and if yes, on the onset date and time.
For ketoacidosis, the CEC was to decide for the events sent for adjudication on the case definition classification
according to the charter (certain, potential, unlikely, ‘unlikely but ketosis’, or unclassifiable), severity (mild,
moderate, severe, or not assessable), and outcome (recovered, sequelae, or fatal). The tasks and responsibilities of
the CEC were specified in the CEC Charter for Ketoacidosis and Severe Hypoglycaemia Events.
Hepatic external adjudication:
Certain hepatic events were adjudicated by external independent experts and categorised for severity (no hepatic
injury, mild to moderate hepatic injury, other significant hepatic injury, hepatic failure, or fatal cases) and causal
relationship with the trial medication (unlikely, possible, probable, or indeterminate) in a blinded fashion. The
events which were reviewed were defined in the charter. Events may have been defined by abnormal laboratory
values and/or relevant adverse events (AEs). For events qualifying for adjudication, relevant source documents
generated from any medical evaluations of these events were requested, including laboratory values, histological
analysis, results of ultrasound, CT, MRI, scintigraphy, hospital discharge letters, and medical reports from other
physicians. All evaluations were performed in a blinded fashion. The Hepatic External Adjudication Committee
(EAC) Charter.
Clinical Event Committee – adjudication of cardiovascular events:
An independent external committee (CEC) was established to centrally adjudicate potential cardiovascular events
in a blinded fashion based on the FDA guideline (2). The CEC consisted of 2 subcommittees: CEC Cardiology
(CECC) for the adjudication of fatal and non-fatal events suspected of myocardial ischaemia and heart failure and
CEC Neurology (CECN) for the adjudication of events suspected of stroke (fatal and non-fatal strokes as well as
transient ischaemic attacks [TIA]). The criteria for a trigger event to be sent for adjudication and the definitions of
the cardiovascular end points are defined in the CEC charter. The CEC evaluated whether prespecified criteria for
adjudication end points were met. For any events that qualified for adjudication, trial sites were asked to provide
clinical documentation such as electrocardiograms (ECGs), laboratory values, angiography, echocardiography
reports, CT and/or MRI scans, discharge summaries, and autopsy reports to support the external event
adjudication. The tasks and responsibilities of the CEC were specified in the CEC Charter.
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
EASE-2 AND EASE-3 PRIMARY, KEY SECONDARY AND SAFETY END POINTS
EFFICACY – The Primary end point was:
The primary end point was the change from baseline in HbA1c at Week 26.
EFFICACY – The key secondary end points were:
Rate per patient-year of symptomatic hypoglycemic AEs with confirmed plasma glucose (PG)
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
STATISTICAL ANALYSIS DETAILS AND TESTING HIERARCHY
EASE-2:
For the primary end point, restricted maximum likelihood estimation based on mixed-effect model for repeated
measures (MMRM) analysis was used to obtain adjusted means for the treatment effects. This model included the
fixed categorical effects of treatment, pre-existing insulin therapy, week, and treatment-by-week interaction, as
well as the continuous, fixed covariates of baseline HbA1c, baseline eGFR, and baseline HbA1c-by-week
interaction. Patient was included as random effect. The primary treatment comparisons were the Bonferroni-
adjusted contrasts between each dose of empagliflozin (10 mg or 25 mg) and placebo, with each dose tested at the
level of α=0.025 (2-sided).
The primary efficacy analysis included on-treatment data only, based on the full analysis set (FAS) and observed
cases (OC). Subsequently, an effectiveness analysis (on- and off-treatment data) was performed in a hierarchical
manner, based on the modified intention-to-treat set (mITT) and including data after treatment discontinuation
(OC-AD). If the null hypotheses were rejected for both the efficacy and effectiveness analyses, then the key
secondary end points were to be tested in a confirmatory way using a gatekeeping approach, with unequal
splitting of the α, and sequential testing as depicted below:
The 2 key secondary hypoglycemic AE-related end points were analyzed using a negative binomial model. The
model included treatment and pre-existing insulin therapy as discrete fixed effects, baseline rate, baseline HbA1c,
and baseline eGFR as continuous fixed effects, as well as logarithm of time at risk as an offset. The primary
treatment comparisons were the rate ratios comparing the rates per patient-year of each dose of empagliflozin with
placebo.
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
The key secondary end points of change from baseline in body weight, TDID, SBP, and DBP were analyzed using
an MMRM model similar to the analysis of the primary end point, with the additional covariate of the respective
baseline parameter and using the interaction between the respective baseline parameter and week.
The key secondary end points of change from baseline in the percentage of time spent in target glucose range and
IQR were analyzed using analysis of covariance (ANCOVA), with terms for treatment, pre-existing insulin
therapy, continuous baseline HbA1c, continuous baseline eGFR, and continuous baseline of the respective CGM
end point.
No interim analysis was planned or conducted.
EASE-3:
For the primary end point, restricted maximum likelihood estimation based on mixed-effect model for repeated
measures (MMRM) analysis was used to obtain adjusted means for the treatment effects. This model included the
fixed categorical effects of treatment, pre-existing insulin therapy, week, and treatment-by-week interaction, as
well as the continuous, fixed covariates of baseline HbA1c, baseline eGFR, and baseline HbA1c-by-week
interaction. Patient was included as random effect. The primary treatment comparisons were the Bonferroni-
adjusted contrasts between each dose of empagliflozin (10 mg or 25 mg) and placebo, with each dose tested at the
level of α=0.025 (2-sided).
The primary efficacy analysis included on-treatment data only, based on the full analysis set (FAS) and observed
cases (OC). Subsequently, an effectiveness analysis (on- and off-treatment data) was performed in a hierarchical
manner, based on the modified intention-to-treat set (mITT) and including data after treatment discontinuation
(OC-AD). If the null hypotheses were rejected for both the efficacy and effectiveness analyses, then the primary
efficacy end point for empagliflozin 2.5 mg versus placebo and the key secondary end points were to be tested in
a confirmatory way using a gatekeeping approach, with
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
unequal splitting of the α, and sequential testing as depicted below
The 2 key secondary hypoglycemic AE-related end points were analyzed using a negative binomial model. The
model included treatment and pre-existing insulin therapy as discrete fixed effects, baseline rate of hypoglycemia,
baseline HbA1c, and baseline eGFR as continuous fixed effects, as well as logarithm of time at risk as an offset.
The primary treatment comparisons were the rate ratios comparing the rates per patient-year of each dose of
empagliflozin with placebo.
The key secondary end points of change from baseline in body weight, TDID, SBP, and DBP were analyzed using
an MMRM model similar to the analysis of the primary end point, with the additional covariate of the respective
baseline parameter
No interim analysis was planned or conducted.
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
DEVICES USE: BLOOD GLUCOSE-KETONE METER, E-DIARY AND CONTINUOUS GLUCOSE
MONITORING
Self-blood glucose and ketone monitoring:
From the beginning of the T1D therapy optimization period until the end of the follow-up period, all patients were
to be provided with a blood glucose monitoring device/meter that was also capable of measuring blood ketones
(beta-hydroxybutyrate [BHB]) for use at home during the trial for self-measurement of blood glucose and BHB
levels. Instructions on the proper use of this point of care device were to be provided by the site staff. The patient
was asked to enter data from the glucose-BHB meter in their electronic diary on a daily basis.
Electronic diary (e-diary):
From the beginning of the T1D therapy optimization period until the end of the follow-up period, all patients were
to be provided with an e-diary for daily use during these periods of the trial. Prior to its first use, instructions on
the proper use of the e-diary were provided by the site staff. Refresher training was to be provided at subsequent
time points as deemed appropriate by the investigator or designated site personnel.
Daily entries into the e-diary included at least: glucose values from self-monitoring of blood glucose, any
hypoglycemic events that had occurred, and insulin requirement.
Any ketone measurements performed (beta-hydroxybutyrate value) were also to be entered into the e-diary if and
when any data became available.
Throughout the trial, the investigator and/or designated site personnel were to review the patient’s glucose and e-
diary results to determine if treatment adjustments needed to be implemented. The e-diary data was transferred to
a vendor server for data collection and transfer to the sponsor with a cut-off date of database lock for the purposes
of data analyses.
Continuous glucose monitoring (CGM):
The CGM system was a commercially available system with single-use disposable electrochemical sensing
elements. It allowed glucose levels to be recorded for up to 7 days at a time, after which a sensor change was
required to continue CGM. Glucose values recorded by the CGM system were blinded to the patient and the
investigator/designated site personnel to ensure unbiased data. However, sites were able to access information
regarding the use of the system.
Prior to the first CGM period, patients were trained in the correct use of the CGM system, including its setup,
sensor insertion, exchange, and removal, as well as calibration using the SBGM device. Refresher training was to
be provided at subsequent time points (as deemed appropriate by the investigator or designated site personnel).
Two main periods of CGM were took place (14 days during the placebo run-in pre-treatment period and at several
time intervals spanning 14-28 days during treatment). These durations accounted for the natural variation due to
sleep/wake, eating, and activity patterns. Every 7 days after starting each CGM period, the sensor had to be
exchanged; where a clinic visit was not scheduled for this day, the patient was to change the sensor at home.
Sensors were to be inserted at least 3 inches (7.62 cm) away from insulin infusion sets or injection sites.
The CGM data were transferred to the vendor server for data collection and transfer.
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
SUPPLEMENTARY FIGURE S1. SCHEMATIC DESIGN OF EASE-2 AND EASE-3 TRIALS
Figure Legend: Design of the EASE-2 and EASE-3 trials *CGM was performed as a sub-study of the EASE-3 trial in approximately 30% of patients. CGM, continuous
glucose monitoring. R represents randomization.
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
SUPPLEMENTARY FIGURE S2. CONSORT DIAGRAMS OF PATIENT DISPOSITION IN
EASE-2 AND EASE-3
Figure legend: Patient disposition after 26 weeks (treated set)
Panel A: EASE-2 trial
Panel B: EASE-3 trial
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
Supplementary FIGURE S3. GLYCATED HEMOGLOBIN EFFECTIVENESS ANALYSIS
Figure Legend: Glycated hemoglobin (HbA1c) Effectiveness analysis
Data from randomized patients treated with ≥1 dose of study drug who had a baseline and ≥1 postrandomization
HbA1c measurement (modified intent to treat population).
Panel A: HbA1c from baseline to week 52 (EASE-2) or week 26 (EASE-3). Values at baseline are
descriptive data. Values at weeks 4–52 are based on mixed model repeated measures analysis.
Panel B: Placebo-corrected change from baseline in HbA1c at week 26 (EASE-2 and EASE-3) and week
52 (EASE-2). Data are based on mixed model repeated measures analysis. ***p
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
Supplementary FIGURE S4. BODY WEIGHT - OVER TIME GRAPHS AND ANALYSES
Figure Legend: Weight analyses
Data are from patients treated with ≥1 dose of study drug who had a baseline and ≥1 on-treatment HbA1c
measurement.
Panel A: Weight from screening to week 52 (EASE-2) or week 26 (EASE-3). Values at screening and
week 0 are descriptive data. Values at weeks 1–52 are based on mixed model repeated measures analysis.
Panel B: Change from baseline in weight at week 26 (EASE-2 and EASE-3) and week 52 (EASE-2).
Data are based on mixed model repeated measures analysis.
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
SUPPLEMENTARY FIGURE S5. SYSTOLIC BLOOD PRESSURE – OVER TIME GRAPHS
AND ANALYSES
Figure legend: Systolic blood pressure
Data represent patients treated with ≥1 dose of study drug who had a baseline and ≥1 on-treatment HbA1c
measurement.
Panel A: Systolic blood pressure from baseline to week 52 (EASE-2) or week 26 (EASE-3). Values at
weeks 1–52 are based on mixed model repeated measures analysis.
Panel B: Change from baseline in systolic blood pressure at week 26 (EASE-2 and EASE-3) and week 52
(EASE-2). Data are based on mixed model repeated measures analysis.
SBP, systolic blood pressure.
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
SUPPLEMENTARY FIGURE S6. DIASTOLIC BLOOD PRESSURE – OVER TIME GRAPHS
AND ANALYSES
Figure legend: Diastolic blood pressure
Data represent patients treated with ≥1 dose of study drug who had a baseline and ≥1 on-treatment HbA1c
measurement.
Panel A: Diastolic blood pressure from baseline to week 26 (EASE-3) or week 52 (EASE-2). Values at
weeks 1–52 are based on mixed model repeated measures analysis.
Panel B: Change from baseline in diastolic blood pressure at week 26 (EASE-3 and EASE-2) and week
52 (EASE-2). Data are based on mixed model repeated measures analysis.
DBP, diastolic blood pressure.
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
SUPPLEMENTARY FIGURE S7. EASE-2 AND EASE-3 CGM-BASED GLUCOSE TIME IN
RANGE AND INTER-QUARTILE ANALYSES
Figure Legend:
Time in target glucose range (>70 to ≤180 mg/dL): Change from baseline in time in target glucose
range at week 26 (EASE-2 and EASE-3) and week 52 (EASE-2). Data are from analysis of covariance
(EASE-2 (26 weeks)) or mixed model repeated measures analysis (EASE-2 (52 weeks) and EASE-3 (26
weeks)) in patients treated with ≥1 dose of study drug who had a baseline and ≥1 on-treatment HbA1c
measurement.
Continuous glucose monitoring interquartile range: Change from baseline in interquartile range at
week 26 (EASE-2 and EASE-3) and week 52 (EASE-2). Data are from analysis of covariance (EASE-2
(26 weeks)) or mixed model repeated measures analysis (EASE-2 (52 weeks) and EASE-3 (26 weeks)) in
patients treated with ≥1 dose of study drug who had a baseline and ≥1 on-treatment HbA1c measurement.
CGM, continuous glucose monitoring; IQR, interquartile range.
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
SUPPLEMENTARY FIGURE S8. TOTAL DAILY INSULIN DOSE - OVER TIME GRAPHS
AND ANALYSES
Figure legend: Total daily insulin dose
Data are from patients treated with ≥1 dose of study drug who had a baseline and ≥1 on-treatment HbA1c
measurement.
Panel A: Total daily insulin dose from screening to week 52 (EASE-2) or week 26 (EASE-3). Values at
screening and week 0 are descriptive data. Values at weeks 4–52 are based on mixed model repeated
measures analysis.
Panel B: Change from baseline in total daily insulin dose at week 26 (EASE-2 and EASE-3) and week 52
(EASE-2). Data are based on mixed model repeated measures analysis.
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
SUPPLEMENTARY FIGURE S9. TOTAL DAILY BASAL INSULIN DOSE - OVER TIME
GRAPHS AND ANALYSES
Figure legend: Total daily basal insulin dose.
Data are from patients treated with ≥1 dose of study drug who had a baseline and ≥1 on-treatment HbA1c
measurement.
Panel A: Total daily basal insulin dose from screening to week 52 (EASE-2) or week 26 (EASE-3).
Values at screening and week 0 are descriptive data. Values at weeks 4–52 are based on mixed model
repeated measures analysis.
Panel B: Change from baseline in total daily basal insulin dose at week 26 (EASE-2 and EASE-3) and
week 52 (EASE-2). Data are based on mixed model repeated measures analysis.
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
SUPPLEMENTARY FIGURE S10. TOTAL DAILY BOLUS INSULIN DOSE - OVER TIME
GRAPHS AND ANALYSES
Figure legend: Total daily bolus insulin dose
Data are from patients treated with ≥1 dose of study drug who had a baseline and ≥1 on-treatment HbA1c
measurement.
Panel A: Total daily bolus insulin dose from screening to week 52 (EASE-2) or week 26 (EASE-3).
Values at screening and week 0 are descriptive data. Values at weeks 4–52 are based on mixed model
repeated measures analysis.
Panel B: Change from baseline in total daily bolus insulin dose at week 26 (EASE-2 and EASE-3) and
week 52 (EASE-2). Data are based on mixed model repeated measures analysis.
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
SUPPLEMENTARY FIGURE S11. FASTING PLASMA GLUCOSE – OVER TIME GRAPHS
AND ANALYSES
Figure legend: Fasting plasma glucose
Data represent patients treated with ≥1 dose of study drug who had a baseline and ≥1 on-treatment HbA1c
measurement.
Panel A: Fasting plasma glucose from baseline to week 26 (EASE-3) or week 52 (EASE-2). Values at
weeks 12–52 are based on mixed model repeated measures analysis.
Panel B: Change from baseline in fasting plasma glucose at week 26 (EASE-3 and EASE-2) and week 52
(EASE-2). Data are based on mixed model repeated measures analysis.
FPG, fasting plasma glucose.
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
SUPPLEMENTARY FIGURE S12. WAIST CIRCUMFERENCE – OVER TIME GRAPHS AND
ANALYSES
Figure Legend: Waist circumference
Data represent patients treated with ≥1 dose of study drug who had a baseline and ≥1 on-treatment HbA1c
measurement.
Panel A: Waist circumference from baseline to week 52 (EASE-2) or week 26 (EASE-3). Values at
weeks 12–52 are based on mixed model repeated measures analysis.
Panel B: Change from baseline in waist circumference at week 26 (EASE-2 and EASE-3) and week 52
(EASE-2). Data are based on mixed model repeated measures analysis.
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
SUPPLEMENTARY FIGURE S13. SAFETY ANALYSIS OF HYPOGLYCEMIA DURING
WEEK 1-4 OF TREATMENT
Figure Legend: Hypoglycemia in week 1–4
Investigator-reported symptomatic hypoglycemic adverse events with blood glucose
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
SUPPLEMENTARY FIGURE S14. NET BENEFIT ANALYSIS
Figure Legend: Net patient benefit analysis
Patient net benefit (post-hoc analysis): HbA1c reduction of >0.3%, >0.4% or >0.5% without weight gain,
DKA: Diabetic ketoacidosis or severe hypoglycemia. EASE-3 data up to week 26 are presented for
empagliflozin 2.5 mg and pooled EASE-2 and EASE-3 data up to week 52 are presented for
empagliflozin 10 mg and empagliflozin 25 mg. Data from patients treated with ≥1 dose of study drug who
had a baseline and ≥1 on-treatment HbA1c measurement
-
SUPPLEMENTARY DATA
©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1
SUPPLEMENTARY FIGURE S15. EXPLANATIONS FOR DIFFERENCES IN URINARY
GLUCOSE EXCRETION IN T1D VS T2D
Figure legend:
In T1D vs T2D, an increased state of gl
top related